CCR4 (Chemokine Receptor 4) was first discovered in 1995 by Christine A. Power et al (Christine A. P. et al, J. Biol. Chem., 1995, 270 (8):19495-19500), which is one of members in chemokine receptor (CCR) family, and is a seven-transmembrane G-protein coupled receptor. It has two naturally occurring specific ligands: MDC (Macrophage-derive chemokine) and TARC (thymus and activation regulated chemokine) (Sadatoshi Maeda et al, Veterinary Immunology and Immunopathology 2002 (90): 145-154). The newly discovered chemokine-like factor 1 (Chemokine-like factor 1, CKLF1) is also one of its ligands (Han W. L. et al, Biochem. J., 2001, 357 (Pt1): 127-135).
CCR4 can be expressed in peripheral blood leukocytes, thymus cells, basophils, monocytes, macrophages, platelets, IL-activated NK cells, spleen and brain, and can play an important role in various diseases. For example, when human allergic dermatitis (AD) occurs, CCR4 expressed by CD4+T cells has an increased expression in peripheral blood mononuclear cells (PBMCs), and the level of TARC in serum also correspondingly increases. This shows that the chemotactic response of CCR4 expressed in cells is induced by TARC, and, when human allergic dermatitis occurs, Th2 cells selectively migrate to the damaged skin. The drugs useful for the treatment of allergic dermatitis mainly include antihistamines, bronchodilators, but they can only improve the symptoms, while having no effect on the development of disease. In addition, corticosteroids also have a certain effect for allergic dermatitis, but there is a potential safety hazard. There are studies to show that the antagonism of MDC or TARC can reduce the accumulation of T cells in inflammatory sites, and CCR4 antagonists may be very effective for the treatment of allergic dermatitis.
The expression of CCR4 is increased when rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, etc. occur. By CCR4 it is also possible to make MDC and TARC activate platelet, which suggests that CCR4 may play an important role in platelet activation and thrombotic diseases associated therewith. CCR4 can also be indirectly coupled with HIV-1, and meanwhile it is also a co-receptor of HIV-2.
In addition, CCR4 is also closely related to pulmonary diseases such as chronic obstructive pneumonia, chronic bronchitis and asthma. CCR4 can be restrictively expressed in cells involved in asthmatic reaction, and is considered to be a good target for the treatment of asthma. At present, chemokine receptor antagonists useful for the treatment of asthma that have entered clinical phase I mainly include CXCR2, CXCR4, CCR1 and CCR5 receptor antagonists, but not CCR4 receptor antagonist. Therefore, the development of CCR4 receptor antagonists has a good prospect.